Spirocyclic thienopyrimidines: synthesis, new rearrangements under Vilsmeier conditions and in silico prediction of anticancer activity

Abstract

Aim. To find novel anticancer lead molecules among easily available spiro-fused thieno[2,3-d] pyrimidines. Methods. Organic synthesis, spectral methods and molecular docking. Results. New spiro heterocycles were synthesized by condensation of 2-aminothiophene-3-carbonitriles with cyclic ketones via Gevald reaction. Other model spirocyclic compounds were prepared by the reaction of 3-aminothieno[2,3-b]pyridine-2-carboxamides with cyclohexanone under acidic conditions. According to the docking studies against the EGFR WT the synthesized compounds revealed good binding energies ranging from-8.4 to-10.2 kcal/mol. The compounds were tested as inhibitors of protein kinase CK; 7',8',9',10'-tetrahydro-1'H-spiro[cyclohexane-1,2'-pyrimido[4',5':4,5]thieno[2,3-b]quinolin]-4'(3'H)-one showed the best binding energy while be bound by a hydrogen bond to Val66 amino acid residue. This compound also showed good results as a potential inhibitor of B-Raf kinase. Conclusion. New spiro-fused thieno[2,3d]pyrimidines have been synthesized. The inhibition activity of novel compounds as potential inhibitors of the EGFR, CK2, FGFR1 and B-raf kinases was examined. We found that spirofused thieno[2,3-d]pyrimidines undergo the rearrangement under Vilsmeier-Haack conditions to afford hitherto undescribed thienopyrimidines and-quinolines. The docking studies revealed that the rearranged products do not tend to form hydrogen bonds with the kinase amino acid residues and show moderate binding energies. Therefore, in contrast to the spiro-fused thieno[2,3-d]pyrimidines, the rearranged products cannot be considered as perspective targets for further screening.

Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides

“…Furthermore, this method was applied to 3-imino(thiophen-2-yl)furan-2(3H)-ones derivatives, which include the pharmacophore fragment, Gewald aminothiophene [37][38][39][40][41]. Compounds that contain this pharmacophore fragment exhibit analgesic [42][43][44], anti-inflammatory [45,46], antimicrobial [47][48][49] and photoluminescent properties [50,51] and other biological activities [52][53][54]. Also, we showed that N′-[5-aryl-2-oxofuran-3(2Н)ylidene]furan-2-carbohydrazides and its precursor 4aryl-2-[2-(furan-2-ylcarbonyl)hydrazinylidene] -4oxobutanoic acids have analgesic activity in the previous studies [55].…”